There is increasing evidence in Escherichia coli that certain operons, though scattered on the genetic map and having separate controls, may also be subject to common, global controls that coordinate their expression. In many cases the co-regulated genes share a common regulator molecule and are called a regulon. Co-regulated proteins can be recognized by two dimensional gel electrophoresis that resolves total cellular protein; co-regulated genes can be discovered with the aid of new genetic techniques involving fusing the Beta-galactosidase gene to promoters at random throughout the genome. These and other genetic and biochemical techniques can then be used to identify the proteins, map their genes and analyze the nature of their control. This project is directed at discovering and analyzing the regulons that are involved in the response of E. coli to changes in temperature, phosphate supply, and the availability of molecular oxygen. A shift to high temperature activates a regulon of 13 genes controlled by a single regulatory gene through its protein product. A mutant deficient in this protein dies at temperatures permitting growth of normal cells. Analysis of this regulon and the molecular mechanism of its control is particularly significant because it constitutes E. coli's version of the biologically universal "heat shock" response of cells to high temperature and certain other stress. Deprival of phosphate induces a complex response involving induction of at least 20 operons, and adaptation to grow anaerobically or in the presence of oxygen similarly involves multigene responses. In addition to defining and analyzing the regulons involved in these responses, we shall examine the recent discovery that global control systems overlap. We shall determine the extent of this overlap among the major global control systems of E. coli, learn its molecular basis, and evaluate its role in metabolic integration. Our long range objective is an understanding how the bacterial cell coordinates the thousand or so individual chemical reactions necessary for growth. Analysis of multigenic (global) control systems should help us understand E. coli, where the work is most readily done, and should provide valuable leads to metabolic integration and gene coordination in more complex cells.